Myocardial infarction (MI) is the leading cause of death in the US. Those that survive, frequently go on to develop ventricular dysfunction and heart failure. While revascularization has dramatically reduced mortality after MI, ongoing efforts to develop post-MI cardioprotective therapies that prevent cardiomyocyte cell death have been unsuccessful. Here, we consider an alternative therapeutic approach, limiting the excessive and maladaptive innate immune response to cell death. When cells die, they release danger signals that overlap with the molecular features used by our immune system to recognize pathogens. As a result, MI elicits strong innate immune responses. We found that IRF3, a master regulator of the antiviral response plays an unexpected essential role in the pathogenesis of MI. Mice deficient in IRF3 exhibited significantly less inflammation and were strikingly protected from death after MI compared to wild type mice. We hypothesize that cardiomyocytes and cardiac resident macrophage in the infarct borderzone play unique roles in spreading IRF3-dependent signals, promoting immunologic infarct expansion, and increasing the risk of heart failure and death after MI. The scientific aims of this K99/R00 are to 1) identify which danger signaling pathway is responsible for activation of IRF3 after MI, 2) identify which cardiac cell type(s) are responsible for IRF3- mediated injury and death after MI, and 3) to develop pharmacologic inhibitors of IRF3 activation as a novel class of post-MI cardioprotectants. The long-term goal of these studies is to identify cardioprotectants that can be administered post-MI to limit immunologic infarct expansion and development of chronic heart failure. The applicant is a physician-scientist trained in engineering, innate immunity, and clinical cardiology. This grant will facilitate his transition to investigative independence through 1) structured training in advanced immunology, molecular imaging, biostatistics, responsible conduct of research, and laboratory management; and 2) guidance from a multidisciplinary team of mentors and advisors comprised of experts in clinical cardiology, cardiac immunology, innate immunity, molecular imaging, therapeutics development, and drug delivery.